Summary Cachexia, characterized by muscle wasting, is a lethal complication of cancer seen in more than 50% of cancer patients and the immediate cause of ~30% cancer related death. However, due to the poor understanding of its highly complex etiology, there has been no FDA-approved treatment for cancer cachexia. We recently discovered in mouse cancer models that cancer cell-released circulating HSP70 and HSP90 associated with exosome-type extracellular vesicles (EV) are key inducers of muscle wasting by activating TLR4 on skeletal muscle cells. In addition, elevated circulating HSP70/90 are responsible for the elevation of such catabolic cytokines as TNFa and IL-6 due to their systemic activation of TLR4. These data suggest that elevated circulating HSP70/90 are key inducers of inflammation and muscle wasting, which are the primary features of cancer cachexia. Thus, targeting cancer cell-released EV-associated HSP70 and HSP90 could be an effective therapeutic strategy for cancer cachexia. However, animal models do not always recapitulate complex events that occur in cancer cachexia in humans, it will be important moving forward to verify the roles of elevated circulating HSP70 and HSP90 in human cancer cachexia, which is hindered by the lack of tools to intercept circulating HSP70 and HSP90 in humans. In this R21 application, we propose to test the hypothesis that elevated circulating HSP70 and HSP90 are key inducers of muscle wasting in human cancer cachexia by generating neutralizing antibodies against human HSP70 and HSP90 with high efficacy, specificity, and defined epitopes, and determining whether the antibodies ameliorate muscle wasting in in vitro and in vivo models of human cancer cachexia. If successful, these antibodies can be used in future clinical studies to determine whether intercepting elevated circulating HSP70 and HSP90 ameliorates muscle wasting in cancer patients.